Recently, the number of patients having so-called lifestyle-related diseases such as diabetes mellitus, hyperlipidemia, hypertension, etc. is drastically increasing. These diseases largely result from the fact that a condition of excessive accumulation of fatty tissues, i.e., obesity is increased in the modern society having hyperalimentation and the lack of exercise. Therefore, it is very important to treat/cure obesity. In Japan, obesity is considered as a disorder such as adiposity, and a guideline for positively diagnosing/treating adiposity has been published. That is, patients having a BMI (body mass index) of 25 or more, and further having a health disturbance caused by or relating to obesity, and requiring body weight control, for example, one of the diseases selected from type 2 diabetes mellitus/glucose intolerance, abnormal lipid metabolism, hypertension, hyperuricemia/gout, coronary arterial disease, cerebral infarction, sleep apnea syndrome, fatty liver, orthopedic diseases, and menstruation problems, are diagnosed as adiposity. In addition, patients having no such a health disturbance but patients with visceral fat-type obesity are also diagnosed as adiposity.
In the treatment of adiposity, diet therapy and exercise therapy are usually employed, but when the expected satisfactory effects are not obtained thereby, medication therapy is further employed. As an anti-obesity agent, fat absorption inhibitor, orlistat; central anorectic drug, mazindol, sibutramine, etc. have been known, but none of these drugs is sufficient enough in view of both of medicinal effect and side effects. Under these circumstances, it has been desired to develop a new more effective drug from viewpoint of medicinal effect and side effects.
Neutral fats taken from the diet (triglycerol (TG)) are decomposed by pancreatic lipase in the digestive tract into fatty acid and monoacylglycerol (MG), and form a micell, which is further absorbed into the small intestine epithelial cells. The absorbed fatty acid is further converted into acyl-CoA by acyl-CoA synthetase. Further, diacylglycerol (DG) is synthesized from MG and acyl-CoA by monoacylglycerol acyltransferase (MGAT), and further, TG is synthesized again from DG and acyl-CoA by diacylglycerol acyltransferase (DGAT). The synthesized TG associates with cholesterol ester and apo-protein by microsomal triglycerol transfer protein (MTP) to give chylomicron, which is secreted into the blood through lymph duct and transported into peripheral tissues.
As mentioned above, MGAT catalyzes the reaction of MG and acyl-CoA to produce DG, and plays an important role in the process of fat absorption at the small intestine. However, the purification of MGAT is quite difficult so that the study of MGAT has not been progressed yet, and the identification of gene thereof has been finally completed recently. Until now, three molecular species of MGAT (MGAT1, MGAT2, MGAT3) have been cloned and reported (Non-patent Documents 1 to 5). MGAT1 is expressed in the stomach and the kidney, but not expressed in the small intestine. On the other hand, MGAT2 is highly expressed in the small intestine. Further, the gene of MGAT3 has been reported only in human MGAT3, and expressed specifically in the small intestine. Therefore, it is speculated that MGAT2 and MGAT3 may participate in the fat absorption in the small intestine.
It has been reported that the MGAT activity in the small intestine is elevated in OLETF rats, which show obesity and hypertriglyceridemia, by which the involvement of MGAT with obesity and hypertriglyceridemia has been suggested (Non-patent Document 6). In addition, the increased protein amount of MGAT 2 and the elevated MGAT activity in the small intestine in db/db mice showing obesity, and in DIO (diet induced obesity) mice have been reported, and the involvement of MGAT with obesity is indicated (Non-patent Document 7).
Under these circumstances, the present inventors thought that the fat absorption at the small intestine may be suppressed by inhibiting the MGAT activity at the small intestine, which is effective to obesity, and further they intensively studied and finally found a MGAT-inhibitory compound having fat absorption inhibitory activity.
On the other hand, as a compound having a bicyclic pyrimidine structure, Patent Document 1 discloses 2-[2-(substituted amino)-benzylthio]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4(3H)-one derivatives of the following Chemical formula 1, and Patent Document 2 discloses 2-[2-(substituted amino)benzylthio]-5,6,7,8-tetrahydropyrido-[4,3-d]pyrimidine-4(3H)-one derivatives of the following Chemical formula 2, but R1 of these compounds is restricted to a hydrogen atom or a lower alkyl group. In addition, these compounds are disclosed to be useful as a peptic ulcer agent, but the MGAT inhibitory activity or fat absorption inhibitory activity thereof is not disclosed at all.
wherein R1 and R2 are a hydrogen atom or a lower alkyl group; and R3 and R4 are the same or different lower alkyl group.
wherein R1 is a hydrogen atom, a lower alkyl group, a hydroxyalkyl group or a lower alkoxyalkyl group; R2 is a hydrogen atom or a lower alkyl group; R3 and R4 are the same or different lower alkyl group.
In addition, as a compound having a bicyclic pyrimidine structure, Non-patent document 8 discloses a compound of the following Chemical formula 3, but the substituent of the nitrogen atom of the piperidine nucleus is restricted to a benzyl group, and the pharmacological activities of these compounds have not been disclosed yet.
wherein Bn is a benzyl group, and Et is an ethyl group.    Patent document 1: JP-A-H07-330768    Patent document 2: JP-A-H07-330769    Non-patent document 1: Proceedings of the National Academy of Sciences, 99, 8512-8517, 2002    Non-patent document 2: Journal of Biological Chemistry, 278, 18532-18537, 2003    Non-patent document 3: Journal of Biological Chemistry, 278, 13860-13866, 2003    Non-patent document 4: American Journal of Physiology, 285, E927-E937, 2003    Non-patent document 5: Journal of Biological Chemistry, 278, 13611-13614, 2003    Non-patent document 6: Diabetes Research and Clinical Practice, 57, 75-82, 2002    Non-patent document 7: Journal of Biological Chemistry, 279, 18878-18886, 2004    Non-patent document 8: Heterocycles, 115-126, 2001